Age-related bone loss is associated with an increased risk of osteoporotic fracture and is a characteristic feature of virtually all mammals. Multiple factors including hormonal, genetic, nutritional, and life style contribute to decrements in bone mineral density (BMD) with age. Furthermore, seasonal bone loss has been documented in older women, and has been linked to vitamin D deficiency states. However, recent work has raised questions about the causal relationship between seasonal changes in vitamin D and bone turnover. At The Jackson Laboratory, the Mouse Phenome Project recently reported 4% lower total areal BMD in male and female B6.PWD consomic mice during winter compared to summer, despite a constant diet, established light dark cycles and a steady temperature. These findings were replicated in B6 mice over two consecutive years and were associated with similar seasonal changes in body weight. Our laboratory examined femoral vBMD in B6 female mice by pQCT and found 3% lower density in winter than summer (p<0.01). Serum IGF-I was also lowest in the winter (p<0.0001 vs summer), and biochemical markers of bone turnover suggested an uncoupling between resorption and formation prior to winter onset. Surprisingly vitamin D levels did not vary by season. Thus, we postulate there is seasonal bone loss in B6 laboratory mice. Furthermore, we theorize that a spontaneous genetic knockdown in serotonin N-Acetyl transferase (NAT) activity, which leads to the absence of melatonin synthesis in B6 mice, contributes to a circannual rhythm in skeletal turnover, resulting in winter bone loss. Therefore, the purpose of this R21 is to define the magnitude and mechanism of seasonal bone loss in B6 mice. To accomplish this we propose 2 specific aims: [unreadable] 1-To characterize and compare the extent of seasonal bone loss in B6 (melatonin `deficient') and C3H (melatonin `proficient') male and female mice by DXA, pQCT and uCT over 2 years. Diet, locomotor activity and body composition will also be studied. [unreadable] 2-To define the mechanism(s) for seasonal bone loss by studying histomorphometry, biochemical markers of bone turnover, IGF-I, leptin, prolactin, catecholamines, and pituitary and stromal cell expression studies of clock genes over 4 consecutive seasons in B6 and C3H mice. [unreadable] Understanding the impact of circadian and circannual rhythms on the skeleton will afford greater insight into homeostatic mechanisms controlling bone maintenance. [unreadable] [unreadable] [unreadable]